WHO report calls H5N1 vaccine stockpiling premature

Nov 2, 2006 (CIDRAP News) – A group of influenza experts convened by the World Health Organization cautioned today that governments shouldn't stockpile "pre-pandemic" H5N1 influenza vaccines now, because too little is known about the requirements for an effective vaccine.

The group of 22 scientists, who met for 2 days in September, "agreed that governments should not rush to place orders for pre-pandemic vaccines when so many fundamental scientific questions are still outstanding," says their report.

The United States and some other countries have been stockpiling H5N1 vaccines, despite lack of assurance that they would be effective against a pandemic strain. Switzerland recently announced plans to buy enough vaccine for the entire Swiss population.

The 16-page report, titled "Influenza Research at the Human and Animal Interface," emphasizes the continuing seriousness of the threat posed by the H5N1 virus. The meetings on which it was based involved many of the world's leading experts on influenza.

The experts agreed that "the seriousness of the present situation, including the risk that a pandemic virus might emerge, is not likely to diminish in the near future," the document states.

The report also warns that if the H5N1 virus becomes a pandemic strain, it could remain as lethal for humans as it is now, depending on how it acquires the ability to spread from person to person. The current case-fatality rate, with 256 cases and 152 deaths, is about 59%.

If the virus becomes more transmissible by acquiring genes from a human-adapted flu virus, its deadliness "would most likely be reduced." But if it remains "a wholly avian virus" that adapts to humans through a series of mutations, it could remain as deadly as it is now, the experts say.

The report says that vaccine development results so far "have not been promising," in part because H5N1 viruses have branched off into a number of diverse subgroups, and vaccines that seem to work against one clade, or group, don't work well against others.

Many fundamental questions about vaccine development remain to be answered, the group concluded. For example, scientists need to determine which adjuvant (general immune system stimulant) works best and to define what kind of observed immune response indicates an adequate level of protection against the actual virus.

The experts say the idea of intradermal injection (injecting vaccine just under the skin instead of into muscle) as a way to stretch vaccine supplies "does not look promising and is not likely to be suitable for worldwide use."

The document cites an urgent need for international standards for evaluating the efficacy of pandemic vaccines. "On such an important matter, it is unwise to leave assessments of appropriate vaccines to competing manufacturers," it states.

The report describes human H5N1 disease as "fundamentally different" from ordinary flu, marked as it typically is by progressive viral pneumonia, acute respiratory distress, and sometimes diarrhea and liver dysfunction. The disease's severity may be a result of the "cytokine storm," or flood of chemical messengers causing intense inflammation in the lungs, but it is not clear whether the cytokine storm is the cause or the result of extensive tissue damage and disease.

Some other observations and recommendations in the wide-ranging report are as follows:

A simple, rapid, and reliable diagnostic test for use in the field and at the patient's bedside is urgently needed.

Research is needed to determine what makes children and young adults especially vulnerable to infection.

Recent serologic studies have shown very little evidence of asymptomatic or mild H5N1 infections in humans. All healthcare workers studied in Thailand tested negative, and samples submitted from Djibouti, Nigeria, Kazakhstan, and Mongolia for testing at the US Centers for Disease Control and Prevention were all negative. However, some family members of patients in Vietnam tested positive.

Studies are needed to determine if a genetic predisposition increases the risk of human infection or of human-to-human transmission among blood relatives.

Resistance to the first-choice antiviral drug, oseltamivir, has been seen in a few patients, but studies show a low rate of oseltamivir-resistance mutations in H5N1 viruses in birds. Resistance to amantadine, the second-choice antiviral, varies among H5N1 strains.

Mallard ducks are now seen as the leading vectors in the geographic spread of H5N1; mute swans are highly susceptible to the disease but probably don't spread it.

Regarding poultry outbreaks in China, "the situation is severe and not yet fully under control," and vaccination of the entire poultry population is needed.

To control H5N1 disease in poultry, vaccination, coupled with appropriate monitoring, should be used when culling is impracticable.

Scientists who track the disease in ducks should adjust their sampling procedures to reflect that ducks now shed more virus in their respiratory secretions than in feces.

The experts' warning against stockpiling of H5N1 vaccines was hailed by infectious disease expert Michael T. Osterholm, PhD, MPH, as appropriate advice in view of the virus's genetic variability.

"I think this report will result in a pause in what I think has been a recent epidemic of vaccine results by press release," said Osterholm, director of the University of Minnesota Center for Infectious Disease Research and Policy, publisher of the CIDRAP Web site.

He also said the report makes clear that the risk of a severe pandemic like that of 1918 still exists. "Some have suggested that talking about any kind of pandemic other than [the moderate pandemic of] 1957 or 1968 was tantamount to scaremongering," but the report makes clear that from a virologic standpoint, the H5N1 virus could remain highly deadly while evolving into a pandemic strain, he said.

"This is a really thoughtful report, and it adds a tremendous amount to the ongoing discussion," Osterholm said.